Enzyme structure discovery heralds new drugs for obesity and diabetes

19 December 2013

Scientists have identified the drug binding site in an enzyme
that plays a key role in regulating glucose, fat and cholesterol
metabolism, called AMP-activated protein kinase (AMPK).

The research, led by the Medical Research Council's National
Institute for Medical Research (NIMR; now part of the Francis
Crick Institute), will allow scientists to begin designing
drugs that activate AMPK to treat metabolic disorders such as
obesity and type 2 diabetes.

The NIMR team worked with colleagues from the Medical Research
Council's Clinical Sciences Centre at Imperial College and
AstraZeneca in Sweden.

Matthew Sanders of NIMR explained: "AMPK is important for
maintaining a constant level of energy (in the form of a molecule
called ATP) within the body.

"It achieves this by stopping cells from making and storing fat
and glucose, which use up energy. It also allows cells to burn off
fat and glucose, which produces energy and helps restore the energy
levels within the body.

AMPK is made up of three subunits - called alpha, beta and
gamma. It is activated when ATP levels in a cell decrease. Dr Steve
Gamblin's group at NIMR previously showed that two binding sites in
the gamma subunit are used by regulators of AMPK. And in 2006,
Abbott Laboratories developed a potential drug that activates AMPK,
which showed promise in treating aspects of the metabolic syndrome
- a cluster of metabolic symptoms such as obesity that predispose
people to heart disease and diabetes. However, despite a major
effort since then to work out precisely how the drug activates
AMPK, its specific binding site remained elusive.

In the current study, the researchers identified another
molecule, more potent than the one made in 2006, that binds to and
activates AMPK. They also used X-ray crystallography, which exposes
crystals of the enzyme to X-rays, to determine the 3D structure of
the whole AMPK complex when it was bound to each of the potential
drugs.

This showed that there is a single site for drug binding at the
interface between the alpha and beta subunits - a different site to
those on the gamma subunit used by the enzyme's usual
regulators.

Dr Sanders said: "This is the first time that anyone has been
able to visualise the AMPK drug binding site and it will allow
scientists to design drugs that 'fit' this site.

"The ability to visualise a drug binding site on any drug target
is an enormous step forward for the scientific field and
pharmaceutical industries."

The discovery of a binding site for drugs that activate a key
metabolic enzyme is expected to enable the design of new treatments
for conditions such as obesity and type 2 diabetes.

Metabolic disorders are becoming increasingly prevalent in the
UK as more of the population suffers from conditions such as high
blood pressure, cholesterol imbalance, insulin resistance or
obesity. These symptoms can lead to metabolic disorders including
heart failure and type 2 diabetes. In the UK, 2.9 million people
are estimated to be affected by type 2 diabetes, 2.7 million by
coronary heart disease and 750,000 by heart failure.

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